Antiviral Therapy

Table for antiviral Drug:Viruses: Chemical Type: Target: Acyclovir, VidarabineHerpesviruses (HSV) Nucleoside analogues Virus polymerase GanciclovirCytomegalovirus (CMV) Nucleoside analogue Virus polymerase (needs virus UL98 kinase for activation) Nucleoside-analog reverse transcriptase inhibitors (NRTI): AZT (Zidovudine), ddI (Didanosine), ddc (Zalcitabine), d4T (Stavudine), 3TC (Lamivudine) Retroviruses (HIV) Hepatitis B virus Nucleoside analogue Reverse transcriptase Non-nucleoside reverse transcriptase inhibitors (NNRTI): Nevirapine, Delavridine Retroviruses (HIV) Nucleoside analogue Reverse transcriptase Protease Inhibitors: Saquinavir, Ritonavir, Indinavir, Nelfinavir HIV Peptide analogue HIV protease Ribavirin Broad spectrum: HCV, HSV, measles, mumps, Lassa fever Triazole carboxamide Virus replicase (complex action, direct or indirect) Amantadine / RimantadineInfluenza A strains Tricyclic amine Matrix protein InterferonsHepatitis B and CProteinCell defense proteins activated Zanamavir, OseltamavirInfluenza A and B Substrate analogue Viral neuraminidase Protease Inhibitors: Boceprevir, Telaprivir, Olysio HCVHIV protease

Why is treatment of viral infections so difficult? The problem of selective toxicity –Viruses are eucaryotic Viruses use host cell enzymes –Viruses are obligate intracellular parasites

Olaf and E. coli

How do Dr. Schneewind and E. coli differ? Dr. Schneewind –Has nucleii –80S ribosomes –No cell walls –Human enzymes –Aerobic E. coli –No nuclei –70S ribosomes –Cell walls –Bacterial enzymes –Aerobic, anaerobic and microaerophilic

Olaf and Herpes

How are Herpesviruses and Dr. Schneewind similar? Dr. Schneewind –Has membranes –80S ribosomes –Requires human enzymes –TMI Herpesviruses –Carries an envelope –Uses 80S ribosomes –Requires some human enzymes –Require humans for replication

Why is treatment of viral infections so difficult? Viruses are biologically highly diverse A precise viral diagnosis must be made in order to initiate definitive viral treatment Cellular/tissue damage is often done and viral replication completed before a diagnosis can be made

Influenza virus replication

Acyclovir Guanosine derivative with an acyclic sidechain Prodrug –Requires virus-specific thymidine kinase for activation –Minimal toxicity to non-infected cells

Acyclovir

Acyclovir is a prodrug Acyclovir Acyclovir monophosphate Acyclovir triphosphate Herpes Thymidine Kinase Cellular Kinases

Obligate chain terminator

Acyclovir Active in vitro against all herpesviruses In vivo activity limited –HSV-1 > HSV-2 > VZV > CMV >> EBV Given I.V. or P.O.

Acyclovir- Oral or I.V.? Oral therapy –Mild HSV-1 or HSV-2 disease in immunocompetent patients –Mild VZV in immunocompetent patients –HSV/VZV prophylaxis in immunocompetent or immunocompromised patients Intravenous therapy –Severe disease –Disease in immunocompromised patients –CMV prophylaxis in immunocompromised patients

Acyclovir- Oral or I.V.? All neonatal disease needs I.V. therapy All CNS disease needs I.V. therapy

Acyclovir resistance Most common form is due to thymidine kinase (TK)-deficient HSV Rarely due to DNA polymerase mutants Mutant strains are at a selective disadvantage –Cause disease only in significantly immunocompromised patients who have had protracted courses of acyclovir –Foscarnet is the drug of choice for patients with acyclovir resistance

Valacyclovir Acyclovir has poor oral bioavailability Valyl ester increases oral absorption Serum esterases hydrolyze ester to free acyclovir

Metabolism of valacyclovir to acyclovir

Acyclovir (or valacyclovir) prophylaxis Immunocompetent individuals –Severe recurrences –Frequent reactivations –Periocular/ocular involvement –Personal reasons

Acyclovir (or valacyclovir) prophylaxis Immunocompromised individuals –Severe recurrences –Frequent reactivations –Second episode of shingles –Other reasons Reassess annually

Ganciclovir Nucleoside analog of acyclovir Active in vitro against all herpesviruses Greatest activity against CMV –Also used for HHV-6

Ganciclovir structure

Ganciclovir Mechanism of action not fully understood –CMV UL97 kinase phosphorylates ganciclovir to ganciclovir-monophosphate. –Cellular kinases convert ganciclovir- monophosphate to ganciclovir-triphosphate. –Ganciclovir-triphosphate competitively inhibits the binding of deoxyguanosine triphosphate to CMV DNA polymerase. –Not a chain terminator (“virostatic”)

Ganciclovir- Clinical uses Well documented use in immunocompromised patients –Retinitis, pneumonitis, hepatitis –Possible role in congenital CMV infection Myelotoxic I.V. or P.O.

CMV retinitis

Valganciclovir

Foscarnet Phosphonoformate Phosphorylation not required for activation Inhibits HSV/CMV DNA polymerase

Foscarnet

Primary uses are for treatment of acyclovir-resistant HSV and CMV infections Also used for patients intolerant of ganciclovir

Ribavirin Synthetic nucleoside, structure similar to guanosine Broad spectrum activity against RNA and DNA viruses –Active against RSV, HSV-1 & 2, vaccinia, adenoviruses, parainfluenzaviruses, hepatitis C, influenza viruses A & B, coxsackieviruses, hantaviruses, arenaviruses, togaviruses, HIV-1 Used for RSV, Hepatitis C, Lassa fever

Ribavirin

Ribavirin- Mechanisms of action Prodrug –Phosphorylated Inhibits inosine 5’-phosphate dehydrogenase (part of guanosine synthesis pathway) –Leads to depletion of deoxyguanosine triphosphate and guanosine triphosphate pools Inhibits HIV reverse transcriptase

Possible ribavirin mechanisms of action Direct inhibition of HCV NS5B-encoded RNA-dependent RNA polymerase. Inhibition of capping of viral transcripts. Affects RNA-dependent RNA polymerases –RNA mutagen that drives a rapidly mutating RNA virus over the threshold to “error catastrophe”.

Possible ribavirin mechanisms of action Immune effects –Enhancement of host T-cell-mediated immunity against viral infection through switching the T-cell phenotype from type 2 to type 1.

Ribavirin- Pharmacology Given I.V. or P.O. Primary uses –RSV in infants and immunocompromised patients –Hepatitis C (previously with interferon, now in some DAA cocktails)

Influenza virus structure

Influenza neuraminidase inhibitors Zanamavir Oseltamavir

Oseltamivir

Zanamivir

Neuraminidase inhibitor

Neuraminidase inhibition

Zanamavir inhibits release of influenza virions from infected cells ControlZanamavir

Amantadine and Rimantadine

Amantadine and Rimantadine- cont. Block influenza A uncoating –Block nucleocapsid release into cytoplasm –Inhibit fusion of viral and endosomal vesicle membranes –Bind to M2 protein –Prevent vacuolar acidification

Amantadine and Rimantadine Indicated for treatment and prophylaxis of influenza A only Amantadine associated with CNS side effects, rimantadine less so Not widely used Amantadine is cheap Resistance problems

Interferons Class of natural proteins produced by cells of the immune system –Glycoproteins –Cytokines Respond to immune challenges –Viruses, bacteria, parasites and tumors

Interferons There are three major human interferons: alpha, beta, and gamma. –Interferon alpha has most antiviral activity Grouped into types 1 and 2 (third group described)

Interferons Interferons generally have several effects –Antiviral –Antioncogenic properties –Macrophage activation –NK cell activation –Increased expression of MHC classes I and II –Interferon-α is secreted by B and T cells –Interferon-β is secreted by fibroblasts –Interferon-γ is secreted by T-cells and natural killer lymphocytes.

Interferons (Interferon alpha) Uses –Chronic hepatitis C (previouslyadministered with ribavirin, now obsolete in DAA era) –Chronic hepatitis B –Intralesional injection for HPV-induced lesions

Interferon adverse effects Influenza-like symptoms, especially in the first week of therapy. –Profound fatigue, myalgia, weight loss Bone marrow suppression Increased susceptibility to bacterial infections Depression –Up to 20% of treated patients –Can be profound.

HCV Direct Acting Antivirals -Target a viral protein function. 3 major classes: 1.Polymerase inhibitors, us. nucleoside analogs 2.Protease inhibitors: prevent polyprotein processing 3.NS5A DAAs: affect replication complex formation and virion assembly

Immune and hyperimmune globulins Standard immune globulin Hyperimmune globulins –Varicella zoster immune globulin –Rabies immune globulin –Hepatitis A immune globulin –Hepatitis B immune globulin –Measles immune globulin –CMV immune globulin –Vaccinia immune globulin

“Humanized” murine monoclonal immune globulin Respiratory syncytial virus - Palivuzimab

To remember from the HIV lecture Nucleoside inhibitors: incorporated into replicating DNA strand, chain termination. Non-nucleoside inhibitors: bind the polymerase and inhibit enzymatic activity. Protease Inhibitors: freq. modified peptide like structures that mimic substrate and irreversibly inhibit protease activity